Esters of 5-hydroxytetracyclines

ABSTRACT

ESTERS OF OXYTETRACYCLINES INCLUDING O12A-ESTERS OF OXYTETRACYCLINE, A-AND B-6-DEOXY-OXYTETRACYCLINE, 6-DEMETHYL6-DEOXY-6-METHYLENOXYTETRACYCLINE, THE MERCAPTAN ADDUCTS OF THE LATTER COMPOUND AND ACID ADDITION AND METAL SALTS OF SAID ESTERS AND THEIR UTILITY AS ANTIBACTERIAL AGENTS AND AS INTERMEDIATES IN THE PREPARATION OF OTHER BIOLOGICALLY ACTIVE COMPOUNDS.

United States Patent O 3,579,564 ESTERS F S-HYDROXYTETRACYCLINES RobertK. Blackwood and Manfred Schach von Wittenau, Gales Ferry, (301111.,assignors to Chas. Pfizer & Co., Inc., New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 439,974, Mar.15, 1966. This application Feb. 3, 1969, Ser. No. 796,202

Int. Cl. C07c 103/19, 139/76; C07d 5/20 US. Cl. 260473 15 ClaimsABSTRACT OF THE DISCLOSURE Esters of oxytetracyclines including Q-esters of oxytetracycline, ocand B-6-deoxy-oxytetracycline, 6-demethyl-6-deoxy-6-methyleneoxytetracycline, the mercaptan adducts of the lattercompound and acid addition and metal salts of said esters and theirutility as antibacterial agents and as intermediates in the preparationof other biologically active compounds.

CROSS-REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of copending application Ser. No. 439,974, filedMar. 15, 1965, now abandoned.

BACKGROUND OF THE INVENTION The present invention is concerned with aseries of novel esters of a group of antibiotics and more particularlywith new esters of oxytetracycline, aand fi-6-deoXy-oxytetracycline,6-demethyl 6 deoxy-6-methyleneoxytetracycline, the mercaptan adducts ofthe latter compound, and the acid addition and metal salts of saidesters.

Various esters of oxytetracycline are known. Gordon, in US. Patent2,812,349, issued Nov. 5, 1957, described. the O -monoacyl and O ,O-diacyl derivatives of oxytetracycline. Blackwood, et al., US. Patent3,047,617, issued July 31, 1962, described the O ,O -diacyl derivativesof oxytetracycline, their rearrangement, in the presence of awater-soluble magnesium salt and an alkali metal, to the O ,O --diacylcompounds of the Gordon atent. p SUMMARY OF THE INVENTION The compoundsof the present invention are represented by the formulae I OH OH3,579,564 Patented May 18, 1971 wherein R is selected from the groupconsisting of monoand disubstituted lower alkyl, lower carbalkoxy, halo,phenyl, monoand disubstituted phenyl and furyl,

each substituent of said monoand disubstituted lower alkyl beingselected from the group consisting of lower alkoxy, lower carbalkoxy,and halo, provided that where two of said substituents are joined to thesame carbon atom at least one is lower carbalkoxy,

and each substituent of said monoand disubstituted phenyl being selectedfrom the group consisting of lower alkyl, lower alkoxy, lower carbalkoxyand nitro;

B is hydrogen;

A and B when taken together are methylene;

R and R are each selected from the group consisting of alkanoyloxy,phenoxyalkanoyloxy, lower alkoxyalkanoyloxy, monochloroalkanoyloxy,monobromoalkanoyloxy, dichloroalkanoyloxy and dibromoalkanoyloxy,wherein the alkanoyloxy group has from 2 to 6 carbon atoms;

R and R are each selected from the group consisting of hydroxyl,alkanoyloxy, phenoxyalkanoyloxy, lower alkoxyalkanoyloxy,monochloroalkanoyloxy, monobromoalkanoyloxy, dichloroalkanoyloxy anddibromoalkanoyloxy, wherein the alkanoyloxy group has from 2 to 6 carbonatoms;

and the acid addition and metal salts thereof.

The present invention includes the esters of oc-6-d6OXY- oxytetracyclineand ,8-6-deoxy-oxytetracycline and the acid addition and metal saltsthereof. In the former compound the stereochemistry of the 6-methylgroup is opposite to that of the known 6-deoxytetracyclines produced bycatalytic hydrogenolysis of oxytetracycline (J. Am. Chem. Soc. 80, 5324,1958). These novel esters are represented by Formulae IIV wherein R R Rand R are as previously defined, A is methyl and B is hydrogen. The aand18-6-deoxy-oxytetracyclines thus differ by virtue of the specificconfiguration of the groups at C-6. The stereochemistry of the otherasymmetric centers of the compounds of the present invention is notindicated as a matter of convenience but does correspond, as thoseskilled in the art will appreciate, to that of the precursor from whichthe present compounds are derived. It is obvious, of course, that when Aand B are taken to represent a methylene group, the stereochemistry atC-6, as indicated in Formulae II and IV, no longer exists.

The novel esters of this invention are useful as antibacterial agentsand as intermediates in the preparation of other biologically activesubstances.

The novel O -monoacyl compounds described herein are useful asintermediates for the preparation of polyacylated oxytetracyclinederivatives such as the 0 ,0 diacyland the O ,O ,O -triacyl derivativesby the processes of US. 2,812,349 and 3,047,617. They are especiallyuseful for the formation of polyacyl derivatives having different acylgroups at the O and 0 and/or Q -positions. Further, the herein describedesters of oxytetracycline can be catalytically hydrogenated, e.g., underacid conditions with palladium, or other noble metal catalyst, to thecorresponding epimeric 6-deoxyoxytetracycline esters described herein.'Hydrogenation of the 6-demethyl 6 deoxy 6 methyleneoxytetracyclineesters of this invention over a noble metal catalyst also yields amixture of the corresponding C-6 epimeric ice esters. Raney nickeldesulfurization of the benzylmercaptan adducts of the6-demethyl-6-deoxy-6-methyleneoxytetracycline esters of this invention,the 13-benzylmercapto-tx-6-deoxy-oxytetracycline esters, the compoundsof Formula II and IV wherein B is hydrogen and A is benzylmercaptomethylleads, almost exclusively, to oc-6- deoxy-oxytetracycline esters.

Mild acid treatment of the esters, e.g., saturated methanolic hydrogenchloride, results in dehydration and formation of 5a,6-anhydro-O-acyl-oxytetracycline.

DETAILED DESCRIPTION OF THE INVENTION The novel O-monoacyl-oxytetracyclines of this invention are prepared byrearrangement of the corresponding o -monoacyl derivatives in an aqueoussolution containing at least about an equimolar proportion, andpreferably two molar proportions, based on the O -monoacyl reactant, ofan alkali metal hydroxide. The rearrangement can also be conducted inmethanolic or ethanolic solution. In such solvent systems, it isadvantageous to use an alkali metal alcoholate in place of an alkalimetal hydroxide principally because of the better solubility of saidalkali metal alcoholates in the alcohols. All the alkali metalhydroxides and alcoholates are operable including those of potassium,lithium and sodium. However, sodium hydroxide is preferred in aqueoussystems and sodium alcoholates in alcoholic systems.

The temperature of the reaction is not critical, a range of from aboutC. to about 500 C. being used. The preferred temperature is from about 0C. to about 25 C.

Although the reaction time is not absolutely critical, prolongedreaction periods should be avoided in order to minimize degradation ofthe desired product. For optimum results, reaction periods of greaterthan two hours appear to offer no advantage. Reaction periods as briefas five minutes in many instances depending, of course, on the O-monoacyl reactant produce satisfactory, if not optimum yields ofrearranged product.

Products are isolated by adjusting the pH of the reaction mixture to avalue of from about pH 2-7 and extraction therefrom with a waterimmiscible solvent, e.g., ethylacetate, and recovered therefrom by knownmethods. Frequently, when operating at the upper part of this pH range,part of the product precipitates and can be recovered by filtration orcentrifugation, if desired.

The degradation of the esters, reactant, and product can be avoided, orat least minimized, by conducting the rearrangement in the presence offrom about 1 to about 2 equivalents of a solvent soluble polyvalentmetal salt. This permits a further embodiment of this process, thepolyvalent metal stabilizing the esters through chelate formation. Awide variety of polyvalent metal salts, indeed all polyvalent metalsalts soluble in the reaction solvent can be used. From a practicalstandpoint, however, it is important to employ solvent soluble salts,the O -monoacy1 chelates of which can readily be decomposed to providethe metal-free O -monoacylated compounds. The favored polyvalent metalsalts are those of calcium, magnesium, zinc, cadmium, copper, nickel,and cobalt. Of these, magnesium salts are preferred. Suitable magnesiumsalts for use in aqueous systems include chloride, sulfate, nitrate,acetate, formate bromide, chlorate, and iodide, but particular successhas been achieved employing magnesium chloride hexahydrate. Othersuitable magnesium salts include the propionate, butyrate, citrate,salicylate, sulfocarboxylate, benzoate, lactate, dithionate,ferricyanide, ferrocyanide, nitrite, perchlorate, hydrosulfide,thiocyanate, thiosulfate, fluoride, hydroxide, bromate, iodate, sulfate,tartrate, carbonate, as well as various water soluble double salts, e.g., magnesium ammonium chloride and magnesium ammonium sulfate. Ofcourse, the anion of the magnesium salt must not react with or causedecomposition of the antibiotic. Strongly oxidizing or reducing anionssuch as permanganate are to be avoided.

When a polyvalent metal is present, the products are 4 recovered byprecipitation of the crude metal-ester complexes at a pH of about 6-8.The metal-ester complexes are separated by appropriate methods,resuspended in water, the pH adjusted to about 2-3.5 and the esters extracted into a suitable water immiscible solvent, e.g., ethyl acetate,and recovered therefrom.

As noted, O -monoacyl derivatives are transformed to O -monoacylderivatives by this rearrangement process. It has been found quiteunexpectedly, that when 0 ,0 diacyl derivatives are subjected to thisrearrangement, the acyl group from the O -position is transferred to theQ -position and the O -acyl group is transferred to the O -position.This is established by the rearrangement of O -propionyl-O-acetyl-oxytetracycline to O -propionyl-O -acetyl-oxytetracycline.

The O -monoacyl and O O -diacyl compounds are prepared according to theprocedure of Gordon, U.S. 2,812,349, which comprises the reaction of theappropriate oxytetracycline reactant, the non-esterified forms ofFormula IV, with at least one molar proportion of a carboxylic acidanhydride in dioxane. Alternatively, and preferably, they are preparedby the use of the proper acid chloride in place of the acid anhydride ofGordon from the appropriate 5-oxy and O -acylated oxytetracyclines.Acetone, tetrahydrofuran, the methyl esters of ethylene glycol anddiethyleneglycol and other inert solvents can be used in place ofdioxane although the latter is favored since the hydrochloride salt ofthe oxytetracycline reactant readily crystallizes from this solvent. A1:1 molar ratio of acid chloride to oxytetracycline reactant ispreferred. The reaction is run at a temperature of from about 0 C. toabout 50 C., preferably at from about 15 C. to about 40 C. Reactionperiods of about 3 hours appear to be satisfactory in most instances.Since the hydrochloride salt of the oxytetracycline reactantprecipitates from solution in most instances the extent of reaction canconveniently be followed by measurement of the amount of hydrochloridesalt produced and the reaction period extended, if necessary.

The product is recovered by removing the precipitated hydrochloride saltand adding the mother liquor to a large volume of hexane or othernonsolvent for the ester products. The precipitated crude ester isseparated, suspended in water, the pH adjusted to about 2, the productextracted with ethylacetate and recovered therefrom. Extraction of thethus-obtained product with ether provides a product of good purity whichcan be further purified by recrystallization from a suitable solventsystem.

The O ,O -diacyl and the O ,O ,O -triacyl compounds are prepared by themethod of Blaclcwood et al., U.S. 3,047,617, which comprises treatingone molar proportion of oxytetracycline reactant with from about 2 to 8molar proportions of carboxylic acid anhydride in the presence of fromabout 2 to 8 molar proportions of pyridine at a temperature of fromabout 15 C. to 40 C. Mild hydrolysis of the O ,O -diacyl compoundsaccording to U.S. 3,047,617 produces the Ol -monoacylated products.

It is, of course, obvious that mixed esters can be prepared by furtheresterification of an oxytetracycline reactant which contains at leastone ester group. For ex ample, an O -acetyl derivative can be furtheresterified to an O -propionyl-O -acetyl; or an O -acetyl can beconverted to an O -acetyl-O fl -dipropionyl derivative. The lattertriester can be transformed by hydrolysis of the O -acyl group to an O-acetyl-O -propionyl derivative which in turn can be further esterifiedto a triester having three difierent ester groups.

The 6 demethyl-6-deoxy-6-methyleneoxytetracyclines and the mercaptanadducts thereof utilized as reactants herein are prepared according toU.S. Pats. 2,984,686 (May 16, 1961) and 3,165,531 (Jan. 12, 1965),respectively.

The acid addition and metal salts are prepared by treatment of theherein described esters in an inert solvent with one equivalent of asuitable acid or base. The metal salt complexes are prepared in asimilar fashion. The latter are most suitably recovered by evaporationof the solvent. Such procedure is also applicable to recovery of theacid addition and metal salts, but a somewhat simpler method is to add amiscible nonsolvent for the salt or complex to effect precipitationthereof. The metal salts such as the sodium, potassium, and lithiumsalts are, of course, useful starting materials for the rearrangementprocess described herein. These and other salts, including the acidaddition salts are frequently readily crystallized and thus are usefulforms in which to isolate the desired esters.

The herein described compounds are useful for the same general purposesand in the same general manner as the known parent tetracyclines. The O-monoacylated oxytetracyclines and derivatives thereof described hereinare less active in vitro than are the parent oxytetracyclines but moreactive than the O -monoacylated oxytetracyclines. They do, however,exhibit a rather surprising and unexpectedly high order of in vivoactivity. Indeed, the O monoacyl derivatives of Formulae I-III are thepreferred calculated. The following P'D values are thus obtained for O-acetoxy and O -acetoxytetracyclines (Table H):

TABLE II [PD (mg/kg.) of o -acetoxyand o -acetoxytetracycline] P.multocida S. pyogcner- Tetracycline Oral SQ 1 Oral SQ o -acetoxy Z 50 44O -acetoxy 3 100 100 100 85 l SQ=Subcutaneous route of administration.

3 Nitrate salt used. 8 Sulfate salt used.

compounds of this invention because of their superior oral absorption asdemonstrated by tests in mice. Those compounds having an rat-orientationof the substituent group A at C6, Formulae II and IV, are of particularinterest and generally favored over the corresponding B-epimers ofFormulae III and V by reason of their higher order of activity against avariety of micro-organisms.

The in vivo activity of O -acetyl oxytetracycline is demonstrated byproducing acute experimental infections in mice by the intraperitonealinoculation of the mice with a standardized culture of Pasteurellamultocida or Steptomyces pyogenes suspended in blood broth. Infectionseverity is standardized so that the mice receive 1-10 LD doses ofeither organism. [LD z enough organisms to consistently kill 100% of theinfected, non-treated control mice] The test compounds are administeredto the infected mice by a multiple dosing regimen in which the rfirstdose is administered 0.5 hour after inoculation and is repeated 4, 24,and 48 hours later. The mice surviving after the last treatment are heldfor four days and the percent alive is then calculated (Table I):

TABLE I.ANIMAL PROTECTION STUDIES 1 20 mice are run as a positivecontrol using a known positive drug, e.g., tetracycline; an infected,nonmedicated control group of 30 mice is run as a. virulence control. I

3 SQ=Subcutaneous route of administration.

8 Nitrate salt used.

4 Sulfate salt used.

These values are then converted to prohibits and the PD value (the doseof drug required to protect 50% of the treatment mice against theotherwise lethal infection) In addition to the esters mentioned above,other esters can be prepared as described herein in which the alkanoylgroup is substituted with, for example, at least one of the followinggroups: lower acylamino, lower acyloXy, lower alkoxy, lower alkyl anddi(lower alkyl)amino, phenyl, phenoxy, substituted phenyl andsubstituted phenoxy, wherein the substituted is at least one of thegroup halo, lower acyloxy, lower alkoxy, lower acylamino, lower alkyland di(lower alkyl)amino, lower alkyl. The terms lower alkyl, loweracyl, and lower alkoxy include alkyl, acyl, and alkoxy groups havingfrom 1 to 4 carbon atoms. Representative of such groups are thosederived from the following acids: phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, fi-butoxypropionic acid, o-anisoxyacetic acid,p-tolyl acetic acid, p-acetaminophenylacetic acid andp-diethylaminophenylacetic acid. Further, the esterifying group can alsobe derived from chloroformic acid wherein R is one of theabove-mentioned groups; or from di-(lower alkyl)carbamic acid chlorides,or from acids having the formula 0 O R'("Ji )oH, R'i J-oH.-o0oH whereinR is lower alkyl, di(lower alkyl)amino, lower alkoxy, phenyl orsubstituted lower alkyl and substituted phenyl. Additionally(O-arylcarbonyl) derivatives can be prepared by reaction of theoxytetracycline compound with the appropriate aryl isocyanate underanhydrous conditions in an inert solvent as described by Blackwood etal., in US. 2,976,318, issued May 21, 1961. Suitable aryl isocyanatesare the phenyland naphthyl- (aand 19-) isocyanates and the monoanddisubstituted derivatives thereof wherein the substituents are asdefined above.

The following examples are given by way of illustration and are not tobe considered as the sole embodiments of this invention or as limitingthe scope thereof in any way.

Example I.O -acetyl-oxytetracycline To a stirred mixture of 16.7 g. of o-acetyhoxytetracycline (prepared according to Example III of US. 3,047,-617), 200 ml. of water and 19.1 ml. of 1 M aqueous magnesium chloridehexahydrate solution cooled to 10 C. is added 72.4 ml. of 1 M aqueoussodium hydroxide solution. The clear solution which results is allowedto stand at room temperature for one hour. The solution, pH 12.0, isthen adjusted to pH 6.7 with concentrated hydrogen chloride. The solidwhich precipitates is filtered ofl, washed with water, then slurried in400 ml. of water. The slurry is adjusted to pH 2.5 and extracted withchloroform. Evaporation of the dried chloroform extract gives crude O-acetyloxytetracycline.

The product is purified by dissolving in Water (3.5 ml. per 1.15 g. ofcrude) and 0.4 ml. of nitric acid (per 1.15 g. crude). The nitrate saltprecipitates but to insure complete precipitation, the mixture ischilled overnight. The crystalline nitrate salt is filtered off, washedwith ether and dried.

Example Il.O -propionyl-oxytetracycline A mixture of 20.75 g. of O-propionyl-oxytetracycline (prepared according to the procedures ofExamples III and IV of U.S. 3,047,617), 225 ml. of Water and 20 ml. of 1M magnesium chloride hexahydrate solution is cooled to 5 C. Sodiumhydroxide, 100 ml. of 1 M aqueous solution, is added with stirring andthe resulting clear solution allowed to stand at room temperature fortwo hours. The pH is then adjusted to 6.8 with concentrated hydrochloricacid and the solid which forms removed by filtration. The filter cake iswashed with water then slurried in 500 ml. water. Ether (500 ml.) isadded and the pH of the aqueous phase adjusted to 2.8 with concentratedhydrochloric acid. The mixture is thoroughly shaken, the ether layerseparated, and the aqueous phase concentrated to small volume. Theconcentrate is extracted with two 300 ml. volumes of ether and thecombined ether extracts dried over anhydrous sodium sulfate andevaporated to dryness.

The crude O -propionyl-oxytetracycline is slurried in water (100 ml. per4.4 g.) and concentrated nitric acid (1.8 ml. per 4.4 g. crude) added. Aheavy solid forms almost immediately. Fifteen m1. of a solution ofconcentrated nitric acid and water (the same proportions as used above)is added, the mixture stirred at room temperature for 15 minutes thenchilled for 30 minutes. The crystalline product is filtered oil, washedwith a small volume of Water, followed by ether then dried in vacuounder nitrogen. Additional product is recovered from the filtrate byfurther chilling.

Analysis.-Calcd. for C H O N -HNO (percent): 51.81, C; 5.04, H; 7.25, N.Found (percent): 51.11, C; 5.27, H; 6.98, N.

The above procedure is repeated but using in place of O-propionyl-oxytetracycline the following O -alkanoyl-oxytetracyclines: o-phenoxyacetyh, O -methoxyacetyl-, O -Valery O -butyryb, o -caproyl. Ineach case the corresponding O -acyl derivative is produced.

Example HI.O -acetyland O ,O -diacetyl-ot-6- deoxy-oxytetracyclineAmphoteric a-6-deoxy-oxytetracycline (5 g.) is dissolved in 80 ml. ofdioxane by warming. The solution is cooled to room temperature. Aceticanhydride (320 m1.) is added and the solution allowed to stand for 6days at room temperature. The reaction mixture is taken to dryness on arotating evaporator. The residue is taken up in ether (300 ml.) andfiltered. The ether mother liquor is stripped to dryness and the residuestirred with 300 ml. of hexane to precipitate a crude product containingacetyl-, O ,O -diacetyl and unreacted starting material (5.14 g.).

The crude product (5.14 g.) is recovered by filtration, taken up in 50ml. of acetone and clarified. Upon addi- '8 tion of the solution to 85ml. of stirred water, the bulk of the O ,O -diacetyl derivativecrystallizes. The yield, upon filtration, washing with 50% aqueousacetone and drying, is 1.21 g.

The mother liquor is stripped of acetone and freeze dried. The residueis crystallized from refluxing toluene, with use of a Dean-Stark trap toremove water. The 0 acetyl compound is obtained upon cooling. Recoveryby filtration gives 1.12 g. of O -acetyl derivative. Complete conversionof starting material to the O ,O -diester is obtained by extending thereaction time to two weeks.

Example IV.O ,O -diacetyl-fi-fi-deoxy-oxytetracyclinefi-G-deoxy-oxytetracycline (3.8 g.) is dissolved in ml. dioxane andtreated at room temperature with acetic anhydride (300 ml.). Afterstanding for 2 weeks, the mixture is filtered and evaporated to dryness.The residue is taken up in toluene and the evaporation repeated. Theresidue is dissolved in ether-acetone (3:1), decolorized with activatedcharcoal, and again taken to dryness. The residue is extracted withcyclohexane residue remaining after evaporation of the cyclohexanedissolved in ether. Cyclohexane is added to precipitate the productwhich is recovered by filtration. Concentration of the filtrate providesadditional product.

Example V.O ,0 -diacetyl-6-demethyl-6-deoxy-6- methyleneoxytetracyclineAnhydrous 6 demethyl-6-deoxy-6-methylene oxytetracycline (3-6 g.) isdissolved in 380 ml. of dry dioxane under an atmosphere of nitrogen.Acetic anhydride (144 ml.) and dry pyridine (2.16 ml.) are added, themixture seeded with O ,O-diacetyl-6-demethyl-6-deoxy-6-methylene-oxytetracycline from a previouspreparation and stirred at room temperature for one hour and fifteenminutes. The reaction mixture is then filtered, the filter cake washedwith dry dioxane followed by ether, then air dried.

Using the appropriate oxytetracycline derivative, the following 0 ,0-diacyl-oxytetracyclines are similarly prepared. The products, however,are isolated by the addition of hexane to the reaction mixture. Theproduct, generally an oil, remaining after decantation of the hexanesolution is stirred with water. The resulting solid is recovered byfiltration and dried.

'0 o -diacetyl-tx-fi-deoxyl 3 (benzylmercapto) O ,0-dibutyryl-G-demethyl-6-deoxy-6-methylene- O ,O -di(chloroacetyl)-6-demethyl-6-deoxy-6-methy1- ene- O ,O -di (chloroacetyl -a-6-deoxy- O,O -di (dichloroacetyl -B-6-deoxy- O ,O -di (ybromobutyryl -B-6-deoxy- O,O -di B-chloropropionyl) -6-demethyl-6-deoxy-6- methylene O ,O -di(dichloroacetyl) -6-demethyl-6-deoxy-6- methylene- O ,O -di6-chlorocaproyl -Ot-6-deOXY- O LO -di a,a-dichloropropionyl-6-demethyl-6-deoxy- G-methylene- O ,O -di( chloroacetyl-ot-6-deoxy-13-benzylmercapto- O ,0diacetyl-a-6-deoxy-13-(furfurylmercapto) O ,0 -dipropionyl-w6-deoxy- O,O -divaleryl- 0 ,O -dipropionyl-6-demethyl-6-deoxy-6-methylene- O ,O-di (propoxybutyryl -6-demethyl-6-deoxy-6- methylene- 0 ,O-diacetyl-a-6-deoxy- 1 3 (acetylmer capto) O ,O -diacetyl-ot-6-deoxy-13- (n-dodecylmercapto O ,O -dipro pionyl-u-fi-deoxy-l3-(issooctylmercapto) 0 ,0 -dicaproyl-m--deoxy- O ,O="-diisovaleryl-a-6-deoxy- 0 ,O -diacetyl-a-6-deoxy-13-(methylmercapto)- O ,O -di (phenoxyacetyl -,B-6-deoxy- 9 O ,O -di(methoxyacetyl -p3-6-de oxy- O ,O -di ,B-butoxypropionyl O ,O -di(B-phenoxycaproyl O ,O -di (methoxyacetyl) O ,O -di(phenoxyacetyl) O ,O-di- (w-propoxybutyryl O ,O -di a-phenoxyvaleryl ,O -diacetyl-u-6-deoxyl3- (phenylmercapto) O ,O -di- (me thoxy acetoxy) -ot-6-deoxy-1 3-(trifluoromethylmercapto) O ,O -di phenoxyacetyl -a-6-deoxy- O ,O -di-(w-phenoxypropionyl -a-6-deoxy- O ,O -di- (methoxyacetyl-6-demethyl-6-deoxy-6 methylene- O ,O -di bromoacetyl -a-6-deoxyl3-methylmercapto- Example VI.O -acetyl-6-demethyl-6-deoxy-6-methylene-oxytetracycline O ,O diacetyl 6 demethyl 6 deoxy 6methylene-oxytetracycline (20.7 g.) is added to a solution of 450 ml. ofwater and 12.4 ml. of 29% ammonium hydroxide. The mixture is stirred atroom temperature for 35 minutes at the end of which time 100 ml. ofethylacetate is added and the pH adjusted to pH 4.5 and extracted withfour 75 ml. portions of ethylacetate. The combined ethylacetate extractsare dried over anhydrous sodium sulfate, then evaporated to dryness. Theresidue is taken up in ether and evaporated to dryness to give the solidO -acetyl derivative.

By means of this procedure, the remaining O ,O diacyl derivatives ofExample V are hydrolized to the corresponding O -acyl derivatives.

Example VII.O -acetyl-6-demethyl-6-deoxy-6- methylene-Oxytetracycline 6demethyl 6 deoxy 6 methylene 0 acetyloxytetracycline (3.15 g., preparedaccording to Example VI) is mixed with 30 ml. of water and the mixturecooled at 5 C. Sodium hydroxide (15 ml. of 1 M aqueous solution) isadded and the mixture stirred at 5 C. for ten minutes. Ethylacetate (50ml.) is added and the pH adjusted to 4.5 with hydrochloric acid. Thesolid which forms at the interface is filtered off and the ethylacetatephase separated. The aqueous phase is extracted with three 25 ml.volumes of ethylacetate, the ethylacetate extracts combined, washedtwice with 5 ml. of 0.01 N hydrochloric acid, then dried over anhydroussodium sulfate. The dried ethylacetate is treated with charcoal,filtered and evaporated to dryness to give the desired ester.

Repetition of the above procedure but substituting the O acylderivatives of Example VI for 6-demethyl-6- deoxy-6-methylene Oacetyl-oxytetracycline produces the corresponding O-acylated-oxytetracyclines.

Example VIII-O -acetyl-oxytetracycline The procedure of Example I isrepeated but using the following metal salts in place of magnesiumchloride hexahydrate. In each instance the desired ester is produced.

magnesium sulfateadmium chlorate .2H O magnesium citratecadium formate.2H O calcium chloridecopper (II) bromide calcium nitratecopper (II)sulfate .5H O zinc acetatecobalt (II) acetate zinc chloridecobalt (II)iodide Example IX.O -acyl-oxytetracyclines Two equivalents ofmethoxyacetyl chloride is added to a solution of 0.005 mole of6-demethyl-6-deoxy-6-methylcue-Oxytetracycline in 25 ml. of dry dioxane.The mixture is stirred thoroughly, allowed to stand at room temperaturefor three hours, then filtered to remove the hydrochloride salt of theOxytetracycline reactant. The filtrate is gradually added to 300 ml. ofhexane with stirring. The crude product is filtered off, washed withhexane and suspended in 40 ml. of water-ethylacetate (1:1). The pH islowered to 2, the mixture thoroughly mixed and the ethyl aceate layerseparated. The extraction is repeated (5 X 10 ml.) and the combinedextracts Washed with water (3X1 ml.), dried over anhydrous sodiumsulfate and decolorized with charcoal. The solvent is removed and theresidue stirred with ether (300 ml./ gm. of product) for up to 18 hours.The ethereal solution is removed and evaporated to dryness to give theproduct.

Further purification, if necessary or desirable, is achieved bycrystallization from one or more of the following systems:

chloroform chloroform plus hexane chloroform plus benzene waterisopropyl alcohol plus Water ethanol (or methanol) plus water1,2-dimethoxyethane plus Water methanol-l-one equivalent of sulfuricacid (provides sulfate salt) The following O -acyl-oxytetracyclines areprepared by this procedure from the appropriate reactants:

O -acetyl-a-6-deoxy-1 3- 2,6-dimethylphenylmercapto O-butyryl-a-6-deoxy-13-(B-butoxyethylmercapto) O -acetyl-u-o-deoxy-13-(2,3-dichloropropylmercapto)- O-valery1-a-6-deoxy-13-(4-carbomethoxyphenylmercapto O-butyryl-a-6-deoxy-13- (carbobutoxymethylmercapto O-phenoxyacetyl-6-demethyl-6-deoxy-6-methylene- O-B-phenoxypropionyl-6-demethyl-6-de0xy-6-methylene- O-w-phenoxycaproyl-6-demethyl-6-deoxy-6-methylene- O-fi-butoxybutyryl-6-demethyl-6-deoxy-6-methylene- O -methoxyacetyl- O-phenoxyacetyl- Example X The O -acyl-oxytetracyclines of Example IX arerearranged to the corresponding O -acyl derivatives by the procedure ofExample VII.

Example XI.O -methoxyacetyl-oxytetracycline Anhydrous oxyptetracyclinebase (368 g., 0.8 mole) is dissolved in 4 liters of dry dioxane (driedover Linde 4A Molecular Sieve, produced and distributed by the LindeCompany). To this solution there is added methoxyacetyl chloride (0.4mole, 36.8 ml.). The solution is stirred for six minutes and thenallowed to stand at room temperature for 3.5 hours. Oxytetracyclinehydrochloride g., 38%) is recovered by filtration with a dioxane wash.The crude ester, recovered by freeze drying the mother liquor, isdissolved in 1400 ml. of water. Ethyl acetate (1400 ml.) is added and(with stirring) the pH of the aqueous layer adjusted to 5.0 with 2 Naqueous sodium hydroxide. The ethyl acetate layer is separated and theaqueous layer Washed with three additional 1 liter portions of ethylacetate. The combined ethyl acetate extractions are treated with ca. 20g. of Darco G60, filtered and then dried over sodium sulfate. The ethylacetate solution is stripped to dryness (bath temperature, 40 C.). Theresidue is taken up in 5 liters of chloroform, filtered, seeded, andheld at room temperature for four hours. The crystalline product isrecovered by filtration and Washed with chloroform. The yield of airdried O -methoxyacetyl-oxytetracycline is 139.7 g. (33% based onOxytetracycline, 66% based on actual stoichiometry) Example XII.-O-methoxyacetyl-oxytetracycline nitrate O -methoxyacetyl-oxytetracycline(148.9 g.) is dissolved in a mixture of 800 ml. of water and 1500 ml. ofethyl acetate. The two-phase solution is cooled to 0-5 1 1 C. by meansof an ice bath. Aqueous 1 N sodium hydroxide (700 ml.) is added whilemaintaining the temperature below 10 C. The cold solution is stirred anadditional 5 minutes then adjusted to pH 4.8 with hydrochloric acid. Theethyl acetate layer is separated and the aqueous phase extracted withethyl acetate (3X1 liter). The combined ethyl acetate solutions are backwashed twice with 250 ml. portions of 0.01 N hydrochloric acid, anddried over sodium sulfate. The ethyl acetate solution is stripped todryness and dried by addition and re-evaporation of ether.

In like manner, the following O -acyl-oxytetracyclines are prepared fromappropriate reactants:

O a-chlorobutryl O -chloroacetyl-6-deme'thyl-6-deoxy-6-methylene- 5 O-(6-brornocaproyl)-B-6-deoxy- 0 (dchloropropinoyl)-p-6-deoxy- Ooc-bromobutyryh- 0 -(oc-chloropropionyl)- x6-deoxy-l3-(benzylmer- Theyield of crude base is 111.3 g. (75%). 2

A typical crystallization of O -methoxyacetate as the 0 nitrate was asfollows: Crude base, 95 g. is dissolved in l P I Y i liter of acetone,filtered and washed with acetone to a total i F volume of 1.8 liters ofacetone. To the stirred mother 15 O1a"hehloroaeetyl-ah-deexlh liquorthere is added 17.9 ml. of concentrated nitric acid. 0 h The solution isseeded and stirred for minutes, and the y ty1-6-de0xy-6-methyleneproduct recovered by filtration. It is washed wellwith 5 1 acetone and finally reslurried in ether. The yield is 55.4Example XIV' 0 'chlomacety 'oxytetracychne nitrate A 13? g g: gl t 5 321 frtom olza'esten- 20 O -chloroacetyl-oxytetracycline (10.72 g., 0.02mole) calazgslsfgrovg He sO 3 ilnlcgloli za ercem) c Esilurrigd5W6tt6r1(4(%01m;i; at 5(;dCc.1Aq(l1.l(])1llS sodium 2528112 3 yroxie.m.o isa e an temixture i" 2 Found (Percent): 48-68; stirred for tenminutes at 5 C. Ethyl acetate (400 ml.) is then added and stirringcontinued for an additional five Example XIII.O-chloroacetyl-oxytetracycline 25 a i g? F3 i f s; qg g gi g i ig hg c ne ra e l'lC am 1 m g. e To a S luti n f anhydrous y e lf base ethylacetate phase is separated and the aqueous phase ex- -a e) 1h drydlOXahe hter) afided Chloro' tracted with ethyl acetate (3x150 ml.). Thecombined e y ehlorlde The miXhlFe 15 Fred for five ethyl acetatesolutions are back Washed with water (3 x 10 minutes then held at roomtemperature for 3.5 hours. The m dewlorized with Dame 50 filt r d anddried Over hipg g i gnggvg s t lzgyfl i t fdggfggg gleg guitg gifi a sganhydrous.j sodgim sulfate. The6d9r7y soluftion cils filtered and tevaporate to ryness to give g. 0 cru e ester. liqu r are C m ln andadded to heXaIle l The The product is then dissolved in dry dioxane (150ml), resultmg p p e crude ester is filtered Off, Washed concentratednitric acid added 1.1 ml.), the solution Wlth heXflne and drieduhderhitregell seeded, scratched and allowed to stand. The nitrate saltT crude ester is Slurried In Water ethy precipitates and is filteredoff, washed with dioxane, ether tate (1 liter) added and the pH adjustedto 2.0 with aqued d i d Yi 1d=3 150 OHS sodium hydroxide. The mixture isfiltered and the The remaining Q -esters 0f Example are rearacetatelayer Separate The aqueous Phase is then ranged to their corresponding O-esters by this same protracted with ethyl acetate (3 X300 ml.). Theethyl ace- 40 di re, They are isolated as the nitrate salts. tatesolutions are combined, back washed with water 3X10 ml.), decolorizedwith Darco G60, filtered and Example XV-M1Xed Whom-113C311 denvatlvesdried over anhydrous sodium sulfate. The dry ethyl ace- 12o 1 -6 dy-oxytetracycline (0.005 mole) is gag gunme 1s filtered then pp todrymess below {5 dissolved in 5 ml. of dimethylformamide and3 ml.ofproionic anh dride is added all at once. The mixture is The residue ofPartially Purified ester is Shlfgtirred slovt ly as 1.5 ml. of pyridineis added over a tenried overnight in ether (6 liters). The insolublematerial minute eriod, the temperature being held below 40 C. is removedby filtration and reslurried in ether (3 liters) b external di Thmixture i o l d to 30 C, overhight- The Slurry is filtered and thecombined ether stirred at room temperature for one hour, and the productSOIU'EIOHS evaporated to dryness give crude estel precipitated by theaddition of 4 ml. Water. The product is g-)- The l'esifhle is taken P inchloroform and recovered by filtration and crystallized from methanol.the solution allowed to stand overnight. The crystalline I lik mannerthe following mixed O ho -diacyl product is removed by filtration anddried (18.90 g.). compounds of Formula IV are prepared from the 0 I Ananalytical sample is obtalned by a further recrystal- 5acyl-oxytetracyclines of Examples VI, IX, and XIII using lization fromchloroform. the appropriate acid anhydride:

R2 R3 B4 A B A+B 811% glethoxyacetoxy ghloroacetoxy 11 'g l t on acciiiiiff ri pi iiyioxy oiniscm "if CH2 d Methoxyacetoxylit-CH3 H d0.. fi-OHsH Acetoxy. o-CHi H gd tc fl goowtmscm H I OH Isobutyryloxy "alergi oxy r3 CHHB 2 g Acetoxy Propmnyloxy... CH2 i h ii cioii i ihi i 2 H CHB-Butoxybutyryl ..do "I'" I: I: 11:11:: OH? OH t i g i y fiuggggtlysloxy CiCHZCH(C-1)CH2SCH2 H oii: Acetoxy{i-Phenoiypibpibhylmiv:Eizliiiiifii OEL Butyrylosy AeetoxyC4HQOOHZCHLSCH2 H 8% C hlor haeetoxy iii iii c' 0 60 HES CH2 5 8%:Diotaloroaoetoxy .eetoxgg Z-GH: H

0 2,6-d' rc1n0capr0y1oxy (ll ihih thxynfl C1CHzCH(CL)CHzSCHz H CH2o,o-Dichloropropionylox Phenoxyaeetoxy CH3 Methoxyaoetoxy.Dichloroacetoxy CFSSGHZ H Phenoxyacetoxy Chl0roacetoxy. CH2

TABLEContinued R: R3 R A B A+B B-Phenoxypropionyloxy. Acetoxy CH OHwPhenoxyvaleryloxyu Propionyloxy B-CH3 H Propionyloxy Chloroacetox CHCaproyloxy Acetoxy a-CH3 H Acetoxy Methoxyacetoxy- C4H3OCHSCH H-Bromobutyryloxy Acetoxy B-CH; H Cliloi'oacetoxy d C1H7SCH2 HBr0m0acet0sy P1'0pi0nyloxy CHaSCHz H Acetoxy Chloroacetoxy CgHaSCH H eChloroacetox "do ll-CHS H OH do Acetoxy Example XVI.O ,O-diacyl-oxytetracyclines A mixture of O-acetyl-B-6-deoxy-oxytetracycline (10.6 g.), acetic anhydride (300 ml.)and 300 ml. of dioxane is thoroughly stirred then allowed to stand atroom temperature for two weeks. The reaction mixture is then evaporatedto dryness under reduced pressure. The crude diester is treated with 500ml. of ether and thoroughly mixed. The etheral solution is separated andstripped to dryness to give the crystalline product O ,O -diacetyl-8-6-deoxyoxytetracycline.

Repetition of the above procedure but using the appropriate O-acyloxytetracyclines of Examples VII, X, and XIV and the propercarboxylic acid anhydride produces the following O ,O-diacyl-oxytetracyclines:

O -acetyl-O -propionyl-6-demethyl-6-deoxy-6- methylene- O pro pionyl-O-acetyl-[3-6-deoxy- O -phenoxyacetyl-O -acetyl-cx- 6-deoxy- O-methoxyacetyl-O -propionyl-fl-6-deoxy- O -isovale ryl-O-acetyl-a-6-deoxy- O -acetyl-O -valeryl-a-6-deoxy-13-(acetyl mercapto O-butyryl-O -methoxyacetyl-6-demethyl-6- deoxy-6-methy1ene- O -caproyl-O-acetyl-a--deoxy- O ,O -dicaproyl-a-6-deoxy- O -methoxyacetyl-O-chloroacetyl-[36-deoxy- O -chloroacetyl-O -methoxyacetyl-a-6-deoxy- O-methoxyacetyl-O -dichloroacetylfi-6-deoXy- O -bromoacetyl-O-phenoxyacetyl-a-6-deoxy-13- methylmercapto- O a,c -dichloropropionyl -O-acetyl-6-demethyl- 6-deoxy-6-methylene- O 6-chlorocaproyl) -O-methoxyacetyl-u-6-deoxy- O -acetyl-O -isobutyryl-a-6-deoxy- 13-(benzylmercapto O w-propoxybutyryl -O -acetyl- O -acetyl-O -propionyl-B-6-deoxy- O -propionyl-O -acetyl-u-6-deoxy- O a-phenoxyvaleryl)-O -acetyl-B-6-deoxy- O (methoxyacetyl) -O -propionyl-tx-6-deoxy- 13-trifiuoromethylmercapto) O (w-phenoxypropionyl -O -acetyl-a-6-deoxy- O,O -di u-phenoxyvaleryl -B-6-deoxy- O -acetyl-O -propionyl-u-6-deoxy- 13- acetylmercapto O ,O --diacetyl-a--deoxy- 13 (n-dodecylmercapto O ,O-di methoxyacetyl) -6-demethyl-6-deoxy- 6-methylene- O w-phenoxycaproyl)-O -acetyl-6-demethy1- 6-deoxy-6 methylene- O fi-butoxybutyryl -O -propionyl-6-demethyl- 6-deoxy-6-methylene- O -acetyl-O-(methoxyacetyl)-u-6-deoxy-13- (2,S-dichloropropylmercapto O-chloroacetyl-O -acetyl-a--deoxy-13-benzylmerc ap to- Example XVII.O ,O,0 -triacyl-oxytetracyclines To O-acetyl-6-dernethyl-6-deoxy-6-methylene-oxytetracycline 10.6 g.) andacetic anhydride (300 ml.) in ml. of dimethylformamide at roomtemperature there is added slowly with stirring 5 ml. of pyridine duringa tenminute period. The mixture is then cooled to 30 C., stirred at roomtemperature for 3 hours then treated with an equal volume of water toprecipitate the crude O ,O ,O -triacetylderivative. The product isseparated and crystallized from methanol water.

By means of this procedure the O -acyl-oxytetracyclines of Examples VII,X, and XIV are converted to the following oxytetracycline triacetylderivatives by reaction with the appropriate acylating agent:

0 ,0 ,0 -triacetyl-6-demethyl-6-deoxy-6-methylene- O -acetyl-O ,O-dicaproyl-6-demethyl-6-deoxy- 6-methylene- O ,0 ,O-tricaproyl-a-6-deoxy- O ,O ,O -triacetyl-rx-6-deoxy-1 3-(benzylmercaptoO -butyryl-O ,O -diacetyl-6-demethyl-6-deoxy- 6-methylene- 0 ,0 ,0-triacetyl-B-6-deoxy- O (w-propoxybutyryl -O ,O -diacetyl-G-demethyl-6-deoxy-6-methylene- O ,O ,O -tributyryl-a-6-deoxy- 1 3-(fl-butoxyethylmercapto O -acetyl-O ,0 -diphenoxyacetyl-a-6-deoxy- 13-2, 3-dichloropropylmercapto O ,O ,O --tri chloroacetyl-6-demethyl-6-deoxy- 6-methylene- O -chloroacetyl-O ,o-dimethoxyacetyl-a-6-deoxy- O ,0 ,O -tri (dichloroacetyl) -6-demethyl-6-deoxy-6-methylene- O -dichloroacetyl-O ,O -dipropi0nyl-6-demethyl-6-deoxy-6-methylene- O 6-brom0 caproyl) -O ,O -diacetyl-B-6-deoxy- Oa,B-dichloropropionyl -O ,O -diisobutyryla-6-deoxy- O a-chloropropionyl)-O ,O -diacetyl-a-6-deoxy- 13- (2, 3-dichloropropylmercapto O2,6-dibromocaproyl -O ,O -dicaproyl-a-6-deoxy 2,3-dichloropropylmercapto O -dichloroacetyl-O LO -diphenoxyacetyl-u-6-deoxy- ExampleXV III.O ,O ,O -triacyl-oxytetracyclines A mixture of O ,O-diacetyl-6-demethyl-6-deoxy-6- methylene-oxytetracycline (5.3 g.) andacetic anhydride (300 ml.) in 200 ml. of dry dioxane is stored at roomtemperature for two weeks. The mixture is evaporated to dryness undervacuum at room temperature. The O ,O ,O -triacety1- product is identicalto that prepared in Example XIII.

Utilizing the O ,O -diacyl-oxytetracyclines of EX- amples V and XV asreactants, the following 0 ,0 ,0 triacyl-oxytetracyclines are prepared:

O ,O ,O -triacety1-a-6-deoxy- O -acetyl-O ,0 -diisovaleryl-a-6-deoxy- 15 O -propionyl-O ,O -diacetyl-,8-6-deoxy- O -methoxyacetyl-O ,O-diacetyl-a-6-deoxy- O -phenoxyacetyl-O ,O -diacetyl-a- 6-de0xy' O-butyrylO ,O -di(w-propoxybutyryl -6-demethyl- 6-deoxy-6-methylene- OB-methoxybutyryl -O ,O -diacety1-5-6-deoxy- O -methoxyacctyl-O ,acetyl-O-valeryla-6-deoxy- O -methoxyacetyl-O ,propionyl-O -acetyl-G-demethyl-6- deoxy-fi-methylene- O -phenoxyacetyl-O -acetyl-O -butyryl-G-demethyl-6-deoxy-6-methylene- O -valery-o -rnetho xyace tyl-O -ace tyl-o:-6-deoxy- O ,O -diacetyl-O -propionyl-a-6-deoxyl 3- (benzylmercap to O-valeryl-O -acetyl-O -butyryl-a-6-deoxy-1 3- (fi-b utoxyethylmercapto O,O -di(chlroacetyl)-O -methoxyacetyl-u-6-deoxy- O -meth0xyacetylO ,O-di(chloroacetyl -a6-deoxy- O -acety1-O LO -di(y-bromobutyryl)p-6-deoxy-O -phenoxyacetyl-O ,O -di chloroacetyl -a-6-deoxyl3-benzylmercapto- O-pr0pionyl-O LO -di a,a-dichloroprop1onyl 6-demethyl-6-deoxy-6-methylene- O -acetyl-O -methoxyacetyl-O chloroacetyl-a-6-deoxy- O ,O -dicetyl-o -chloracetyl-w 6-deoxyl 3-phenylmercapto- O ,O,O -tri({3-chloropropiony1) -6-demethy1-6- deoxy-6-methylene- ExampleXIX.O ,O ,0 -triacyl-oxytetracyclines The following triacylatedoxytetracyclines are produced from the O ,O -diacyl derivatives ofExample XVI by the procedure of Example V:

0 ,0 ,0 -triacetyl-B-6-deoxy- O ,O -diacetyl-O-methoxyacetyl-6-demethyl-6- deoxy-6-methylene- O -acetyl-O-phenoxyacetyl-O -valeryl-u-6-deoxyl3- (acetylmercapto O ,-O -diacety1-O-(fi-phenoxypropionyl) -O propionyl-a--deoxy-l 3- (n-dodecylmercapto O,O -diacetyl-O -phenoxyacetyl-a- 6-deoxy- O -meth oxyacetyl-O"-caproyl-O -propionyl-o-6 deoxy-13-(trifluoromethylmercapto) O-propionyl-O -methoxyacetyl-O -acetyla--deoxy- O -acety1-O-phenoxyacetyl-O -propionyl-fi-G-deoxy- O -acetyl-O -butyryl-0-propionyl-a-6-deoxy-13- (acetylmercapto) O ,O -diacetyl-O-chloroacetyl-a-6-deoxy- 0 ,0 -diacetyl-O -dichloroacetyl-a-6-deoxy- O,O -di (u-phenoxyvaleryl -O -chloroacetyl-B-6- deoxy- O ,O -di(bromoacetyl -O -phenoxyacetyl-a-6-deoxyl3-methylmercapto- O6-chlorocaproyl -O -acetyl-O -methoxyacetyla-6-deoxy- O ,O -di(a,u-dichloropropionyl) -0 -acetyl-6- demethyl-6-deoxy-6-methylene-Example XX.Hydrolysis of O ,O ,O -triacyloxytetracyclines The O ,O ,O-triacyl derivatives of Examples XII, XVIII, and XIX are converted tothe corresponding O ,O -diacyl derivatives by the procedure of ExampleVI.

Example XXL-Metal salt formation (A) To one millimole of O-acetyl-oxytetracycline dissolved in the minimum volume ofN,N-dimethylformamide there is added an equimolar proportion of sodiumhydroxide in the same solvent. The mixture is thoroughly stirred and thesodium salt precipitated by the addition of a large volume of ether.

(B) Substitution of the appropriate oxide or hydroxide for sodiumhydroxide produces the corresponding potassium, lithium, calcium,barium, magnesium, zinc, aluminum, ferric, copper, cobalt, and nickelsalts.

(C) The complex salts, that is, the chelates, are prepared by using ametal salt other than the oxide or hydroxide. Thus, using magnesiumchloride, calcium bromide, zinc chloride, cadmium acetate, coppersulfate .5H O, cobalt nitrate or nickel chloride the correspondingchelate is prepared.

(D) Application of these procedures to the remaining esters of thisinvention produces the corresponding salts.

EXAMPLE XXII The acid addition salts are prepared by dissolving thechosen ester in the minimum volume of N,N-dirnethylformamide and addingan equimolar amount of the desired acid. The mixture is stirred and theacid salt precipitated by the addition of several volumes of ether. Thesalt is collected, washed and dried.

By means of this procedure, the hydrochloride, hydrobromide,hydroiodide, nitrate, sulfate, phosphate, p-toluenesulfonate, citrate,acetate, gluconate, bntyrate, benzeate, amsonate, pamoate, stearate,fumarate, maleate, tartrate, laurate and Z-hydroxy-B-naphthoate salt ofthe herein described esters are prepared.

What is claimed is:

1. A compound selected from the group consisting of those having theformulae and the pharmaceutically acceptable acid addition and metalsalts thereof wherein R is selected from the group consisting ofalkanoyloxy, phenoxyalkanoyloxy, lower alkoxyalkanoyloxy,monochloroalkanoyloxy, monobromoalkanoyloxy, dichloroalkanoyloxy anddibromoalkanoyloxy wherein the alkanoyloxy group has from 2 to 6 carbonatoms.

2. The compound of claim 1, Formula I, wherein R is acetoxy.

3. The compound of claim 1, Formula I, wherein R is methoxyacetoxy.

4. The compound of claim 1, Formula I, wherein R is monochloroacetoxy.

5. The compound of claim 1, Formula III, wherein R is phenoxyacetoxy.

6. The hydrochloride salt of the compound of claim 1, Formula I, whereinR is acetoxy.

7. The magnesium salt of the compound of claim 1, Formula I, wherein Ris acetoxy.

8. A compound having the formula and the pharmaceutically acceptableacid addition and metal salts thereof wherein A is selected from thegroup consisting of methyl and YSCH Y is selected from the groupconsisting of primary and secondary alkyl having up to 12 carbon atoms,phenyl, monoand disubstituted phenyl, benzoyl, trifiuoromethyl; R"COwhere R" is alkyl of from 1 to 3 carbon atoms; and R'CH wherein R' isselected from the group consisting of monoand disubstituted lower alkyl,lower carbalkoxy, halo, phenyl, mono-and disubstituted phenyl and furyl,

each substituent of said monoand disubstituted lower alkyl beingselected from the group consisting of lower alkoxy, lower carbalkoxy,and halo, provided that where two of said substituents are joined to thesame carbon atom at least one is lower carbalkoxy,

and each substituent of said monoand disubstituted phenyl being selectedfrom the group consisting of lower alkyl, lower alkoxy, lower carbalkoxyand nitro;

B is hydrogen;

A and B when taken together are methylene;

and R is selected from the group consisting of alkanoyloxy,phenoxyalkanoyloxy, lower alkoxyalkanoyloxy, monochloroalkanoyloxy,monobromoalkanoyloxy, dichloroalkanoyloxy and dibromoalkanoyloxy whereinthe alkanoyloxy group has from 2 to 6 carbon atoms.

9. The compound of claim 8 wherein R is acetoXy, A

is methyl and B is hydrogen.

10. The compound of claim 8 wherein R is butyryloxy and A and B takentogether are methylene.

11. The compound of claim 8 wherein R is phenoxyacetoxy, A is methyl andB is hydrogen.

12. The compound of claim 8 wherein R is methoxyacetoxy, A istrifluoromethylmarcaptomethyl and B is hydrogen.

13. The compound of claim 8 wherein R is methoxyacetoxy and A and Btaken together are methylene.

14. The compound of claim 8 wherein R is monochloroacetoxy, A is methyland B is hydrogen.

15. The compound of claim 8 wherein R is monochloroacetoxy and A and Btaken together are methylene.

References Cited UNITED STATES PATENTS 2,812,349 11/1957 Gordon 260559ATJAMES A. PATTEN, Primary Examiner I. F. TERAPANE, Assistant Examiner US.Cl. X.R.

2x 3"? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent. No.3 579,5 Dated Mg)! 18, 1971 Inventoms) Robert K. Blackwood and ManfredSchach von Wittenau It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 1, line 6, "March 15, 1966" should read Mar. 15, 1965 Col. 3, line29, 500C." should read 50C.

Signed and sealed this 11 th day of September 1 971 (SEAL) Attest:

EDWARD I'LFLETLFHER,JR. ROBERT GOT'ISCHALK Attaining Offloer ActingCommissioner of Patents

